rs759672616
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_000350.3(ABCA4):c.4773+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
ABCA4
NM_000350.3 splice_donor_region, intron
NM_000350.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9991
2
Clinical Significance
Conservation
PhyloP100: 2.77
Genes affected
ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
Variant 1-94021843-T-C is Pathogenic according to our data. Variant chr1-94021843-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 236122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94021843-T-C is described in Lovd as [Likely_benign]. Variant chr1-94021843-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-94021843-T-C is described in Lovd as [Pathogenic]. Variant chr1-94021843-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-94021843-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.4773+3A>G | splice_donor_region_variant, intron_variant | ENST00000370225.4 | |||
ABCA4 | XM_047416704.1 | c.4551+3A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.4773+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_000350.3 | P1 | |||
ABCA4 | ENST00000460514.1 | n.267+3A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152172Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251400Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135902
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GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727210
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74348
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2015 | The c.4773+3 A>G splice site variant in the ABCA4 gene has been previously reported in association with Stargardt disease (Duno et al., 2012; Jonsson et al., 2013; Braun et al., 2013). This variant is predicted to destroy the canonical splice donor site in intron 33. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.4773+3 A>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change falls in intron 33 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs759672616, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 23443024, 23918662, 29555955, 30718709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236122). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28118664, 29162642). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 28, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
Severe early-childhood-onset retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing;in vitro | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 18, 2022 | _x000D_ Criteria applied: PM3_VSTR, PS3, PM2_SUP - |
Retinal dystrophy Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 21, 2019 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -22
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at